My scientific expertise spans as diverse areas as protein biochemistry and biophysics, structural biology and cell biology, as well as single-molecule and single-cell imaging. I have more than 25 years of experience with biochemistry and biophysics of membranes and enzymes, and with scanning probe microscopy (SPM) based imaging methods. I have more than 20 years of experience with biochemistry, cell biology and of structural biology of the proteasome. I worked as a postdoctoral fellow in laboratory of one of founding fathers of the ubiquitin-proteasome field, Dr. A.L. Goldberg (Harvard Medical School). In the laboratories of Drs. Goldberg and Ploegh (MIT Center for Cancer Research) I took major part in discovery of immunoproteasomes and in characterization of first specific inhibitors of proteasome, respectively. As an independent investigator, together with Dr. Osmulski, I took on the vast and novel field of allosteric regulation of the proteasome. The prime interest of the laboratory is to track changes in ubiquitin-proteasome system accompanying cancer and aging, and to use small molecules to affect activity and stability of proteasomal assemblies. Our laboratory laid the groundwork for the use of atomic force microscopy to probe molecular dynamics of the proteasome and its response to drugs, and we are in the forefront of studies on the small-molecule allosteric regulators of the proteasome.

In short, the proteasome is a multifunctional proteolytic enzyme, a focal point of the ubiquitin-proteasome system, essential in cell cycle progression, signal transduction pathways, immune response and general “housekeeping” in the human cell. The proteasome is currently in the center of attention of clinicians and pharmacologists as a surprisingly promising drug target against multiple myeloma and other blood cancers. The mechanism of action of proteasome inhibitors as anti-cancer drugs is not well understood, which impedes their truly efficient utilization to battle the disease, for example to extend the efficient use of proteasome inhibitors in solid cancers. Also, regulation of the proteasome may prove beneficial to help aging cells or to attenuate effects of inflammatory diseases. Our research addresses two major questions fundamental for regulation of proteasome in health and disease.

I. How the proteasomes differ in normal, cancer or aging cells? We propose that proteasome, together with other proteases that take a part in the controlled degradation of regulatory proteins in the cell, constitute a functional entity. They form multibranched degradation pathways enabling a tight control of this irreversible process. We postulate that this web of interactions is dysfunctional in cancer or in aged organisms, creating a "proteolytic instability". Dissecting the web of interaction and aiming at its most vulnerable points would enable to manipulate the activities of the involved proteases to specifically kill tumor cells or to improve an immune response in aging tissue.

II. How to regulate proteasome function in the most effective way? We postulate that molecular dynamics and allosteric signaling are excellent targets for small-molecule regulators capable to affect proteasome function in a truly versatile way. We created a set of peptide and peptidomimetic compounds capable to activate or inhibit the proteasome, to change its specificity, or to synergize with competitive inhibitors.

The capabilities of our laboratory include: 1. Scanning probe microscopy (SPM)/atomic force microscopy (AFM), to study dynamics of biomacromolecules and physical properties of living cells in a single-molecule and single-cell fashion. 2. Spectrofluorometry, for example used to complement the AFM studies of the dynamic structure of the proteasome; 3. Expertise in numerous other spectroscopic methods (EPR, ENDOR, mass spectrometry); 4. Enzymology, including advanced enzyme mechanism and molecular modeling of enzyme-ligand interactions; 5. Development of protein purification techniques designed for giant biomacromolecules; 6. Chemistry of peptides: design and synthesis of peptides, peptide derivatives and peptidomimetics, their purification and characterization, computer modeling of their structure and interaction with intended targets; 7. In addition to the above specialized methods and approaches, we are using standard molecular biology methods, yeast genetics and mammalian tissue culture techniques.

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